A Leptomeningeal Protease Releasing the β Protein from the β Protein Precursor of Alzheimer’s Disease

Abstract

The three characteristic lesions of Alzheimer’s disease are composed of B-pleated sheet fibrils called amyloid. Two of these, the cerebrovascular amyloid deposits and the senile plaques have as their major component a unique protein designated ß protein (ßP)¹ and the fibers denoted as Aß. This unique 28–42 mer polypeptide has also been isolated from the amyloid-laden plaques and vessels in Down’s syndrome (trisomy 21).² This suggested that ßP was encoded by a gene on chromosome 21.² Subsequently the gene for the ßP was identified on chromosome 21 and the deduced amino acid sequence consisted of 695 amino acids, the ß protein precursor (ßPP), and to have characteristics of a membrane associated protein.³ Kunitz protease inhibitor sequences were identified in 751 and 770 mer isoforms of the ßPP. Gene structure provides evidence that the ßP is derived from two exons and thereby arises by proteolytic cleavage of ßPP. Proteolysis has been previously implicated in the creation of amyloid fibrils from the AL and AA types of amyloid disease.⁴